1. Field of the Invention
The present invention relates generally to treatment and prophylactic protocols for cellular diseases or disorders, such as diseases and disorders associated with abnormal cellular proliferation. More particularly, the present invention provides compositions comprising therapeutic antibodies and hyaluronan and their use in the treatment or prophylaxis of cellular diseases and disorders.
2. Description of the Prior Art
All scientific citations, patents, patent applications and manufacturer's technical specifications referred to hereinafter are incorporated herein by reference in their entirety.
Cancer is a hyperproliferative cellular disease which occurs when a cell population replicates in the absence of normal genetic or biochemical control of the cell cycle. In the United States alone, 2,604,650 people died from cancer between 1990-1994, with more men (53%) than women (47%) affected. The most numerous cancer deaths were the result of cancer of the lung (˜30%), colon and rectum (a 11%), breast (˜8%), and prostate (˜6.5%). Among women, the most commonly occurring cancers are breast (31%), lung (12%), colon and rectum (12%), uterus (6%) and ovary (4%).
Historically, cancer treatment generally requires a therapeutic protocol comprising one or more of surgery, radiation and chemotherapy. More recently, therapeutic antibodies directed to cancer targets have been developed. These antibodies are used as parenteral cytoxics and exhibit dose dependant efficacy and toxicity. Systemic chemotherapy is the main treatment available for localized or disseminated malignant disease. Chemotherapy, whether curative or palliative, requires multiple cycles of treatment where chemotherapeutic agents exhibit a dose-response effect and the cell kill correlates to the drug exposure.
The majority of therapeutic approaches to the development of tumor-selective treatments have focused on the morphological and functional differences between malignant and healthy tissues. Drugs designed to manipulate the morphological differences have relied upon the rapid proliferation of cancer cells which coincides with a requirement for an effective oxygen and nutrient supply often fulfilled by the process of neovascularization. The resultant tumor vasculature is defective which allows the penetration of large molecules into the extravascular space and due to the poor intra-tumoral lymphatic drainage there can be a preferential accumulation of large compounds within the malignant site.
The functional requirement for tumor cells to be metabolically efficient and motile results in an over-expression of numerous tumor-specific receptors which can be used as a selective target for the active delivery of anti-cancer agents via specific ligands against these epitopes. One mechanism of overcoming the poor specificity of current cancer therapies has been the use of antibodies which are directed to tumor-specific receptors or molecules, in addition, therapeutic antibodies have the potential to be effective agents in the treatment and prophylaxis of many diseases.
Humanized and deimmunized antibodies have great potential although generally are required to be delivered at a high dose and are expensive to produce. A prerequisite for effective antibody targeting is that antibodies should be able to penetrate tissues. In addition, it is preferable to have a local controlled release method that delivers antibodies to the site of disease. However, formulation challenges often result when coupling antibodies with delivery vehicles. Antibody penetration is a particular problem with tumor-associated therapeutic antibodies and research has also shown that the high affinity fragments can be retained in the periphery of tumors while medium and low affinity fragments appear to gain better penetration. In such cases, non-specific targeting of the antibody can become an issue.
As the development of monoclonal antibodies has moved away from mouse antibodies to chimeric, humanized and deimmunized antibodies, a reduction in anti-antibody response has been observed, however, potential concerns for repeated or chronic treatment exist in a clinical setting. Another possible side effect of antibody therapy is the cytokine release that is mediated through the recruitment of immune effector cells. There is a need, therefore, to develop antibody formulations which may improve efficacy or reduce side effects of antibodies or antibody fragments.